Kuningan, 9 April 2010
Definisi Nyeri (Pain) dari IASP
(International Association for the Study of Pain)
Pain (Nyeri) adalah suatu
pengalaman sensorik dan
emosional yang berkaitan
dengan kerusakan
jaringan atau diduga ada
kerusakan jaringan
Nyeri adalah
pengalaman sensorik
yang berkaitan dengan
aktivasi nociceptor dan
lintasan nyeri
Nyeri adalah suatu
pengalaman emosional
Kerusakan jaringan
tidak mesti ada
JENIS NYERI
Neuropathic Pain
Pain initiated or caused by a
primary lesion or dysfunction
in the nervous system
(either peripheral or
central nervous system)1
Examples
Peripheral
• Post herpetic neuralgia
• Trigeminal neuralgia
• Diabetic peripheral neuropathy
• Postsurgical neuropathy
• Posttraumatic neuropathy
Central
• Posts troke pain
Common descriptors2
• Burning
• Tingling
• Hypersensitivity to touch or cold
Mixed Pain
Pain with
neuropathic and
nociceptive
components
Inflammatory Pain
Pain caused by injury to
body tissues
(musculoskeletal,
cutaneous or visceral)2
Examples
Examples
• Low back pain with
radiculopathy
• Cervical
radiculopathy
• Cancer pain
• Carpal tunnel
syndrome
1. International Association for the Study of Pain. IASP Pain Terminology.
2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57
•
•
•
•
Pain due to inflammation
Limb pain after a fracture
Joint pain in osteoarthritis
Postoperative visceral pain
Common descriptors2
• Aching
• Sharp
• Throbbing
Diagnosis
Drug Treatment
Acute and chronic pain
NSAIDS (al Meloxicam/
Movi-cox), Opioids,
Paracetamol
Myofascial pain
dysfunction
Neuropathic pain,
neuralgias
Analgesics (Movi-cox),
tricyclics, centrally-acting
muscle relaxants,
glucocorticoids
Carbamazepine, phenytoin,
baclofen, tricyclics,
gabapentin, others?
Ascending Pain
Transmission
Pathway
The ascending neural pain pathway is
only a 3 neuron relay
The major convergence point is the
ventral posterior lateral nucleus of the
thalamus, which relays the signal to
limbic and cortical areas
Ascending Pain Pathway (Purves, 2001).
Descending Pain
Modulation
Pathway
The Descending Pain Pathway –
The Periaqueductal Grey (PAG)
is the major convergence point.
Descending pain pathway (Purves, 2001).
Targets of Pain Therapies
Pharmacotherapy
Non-opioid analgesics
Opioid analgesics
Nerve Blocks
Adjuvant analgesics (neuropathic,
musculoskeletal)
Electrical Stimulation
Acetaminofen
Transcutaneous electrical nerve
stimulation (TENS)
Percutaneous electrical nerve
stimulation (PENS)
Alternative methods
(NSAID)
Gottschalk et al., 2001
Acupuncture
Physical Therapy
Chiropractics
Surgery


Thick, myelinated, fast
conducting neurons
Mediate the feeling of initial
fast, sharp, highly localized
pain.
Rabaan
Tekanan


Very thin, unmyelinated, slowconducting
Mediate slow, dull, more
diffuse, often burning pain.
Nerve Fibers
Class
Velocity
Function
A-
A-
Fast
Fast
Motor
A-
A-
Intermediate
Intermediate
B
C
Small
Small
Touch,
pressure
Muscle tone
Pain,
temperature
Motor
Pain
Chemical mediators are released from damaged tissue and
inflammatory cells. Some inflammatory mediators directly activate
nociceptors, while others act together to sensitize the pain
pathway.
Inflammation
l
l
l
biological response to injury or
foreign substances
acute and chronic
inflammation
components:
 cellular response
 biochemical mediators
Mechanisms of Inflammation
Cellular Mechanisms:
 Acute inflammation
PMN
Chronic inflammation
lymphocytes
monocytes
Mechanisms of Inflammation
Biochemical Mediators







vasoactive amines
plasma proteases (complement, kinins)
arachidonic acid metabolites (PG, LT)
lysosomal constituents
oxygen derived free radicals
cytokines
growth factors
Mediators of Inflammation
Arachidonic Acid Metabolites
Prostaglandins
Leukotrienes
Generation of Eicosonoids
Phospholipids
Phospholipase
Arachidonic Acid
5-lipoxygenase
cyclooxygenase
5-HPTE
PGG2
peroxidase
LTB4
LTC4
PGH2
TXA2 PGI2 PGE2 PGF2 PGD2
Biological Effects of
Prostaglandins
PGE2 Vasodilatation, pain sensitization,
gastric cytoprotection
PGF2 Bronchoconstriction, uterine
contraction
PGI2 Inhibit platelet aggregation,
gastric cytoprotection
TxA2 Platelet aggregation
Roles of COX-1 and COX-2
Arachidonic acid
COX-1
“Constitutive”
COX-2
PGs
PGs
· GI cytoprotection
· Platelet activity
· Renal function
Inducible
· Inflammation
· Pain
· Fever
Constitutive
· Renal function
Non-COX selective inhibitors of cyclooxygenase
Selective COX-2 inhibitors
Leukotriene inhibitors
Non-COX Selective NSAIDs
Carboxylic acids
[salicylates, meclofenamate, diflunisal]
Indoleacetic acids
[indomethacin, sulindac]
Propionic acids
[ibuprofen, fenoprofen, ketoprofen,
flurbiprofen]
Naphthalene acetic acids
[naproxen]
Non-COX Selective NSAIDs
[cont’d]
l
l
l
l
l
Diclofenac
Etodolac
Nabumetone
Oxaprozin
Ketorolac
COX - 2 Inhibitors
Celecoxib
l Rofecoxib
l Valdecoxib
l Meloxicam (Movi-cox)*
*[less COX-2 selective]
l
Golongan Coxib



resiko kardiovaskuler + stroke
Physicians prescribing celecoxib or valdecoxib should
consider the emerging cautionary data "when weighing the
benefits against risks for individual patients." The most
appropriate candidates for coxib therapy are patients at a
high risk of GI bleeding or who have a history of intolerance
to "or are not doing well on" nonselective NSAIDs.
"Individual patient risk for cardiovascular events and other
risks commonly associated with NSAIDs should be taken
into account for each prescribing situation."
Consumers should use all over-the-counter analgesics,
"including NSAIDs," strictly according to the label instructions
and consult a physician if using them for longer than 10
days.
Justification for the Development of
COX-2 Selective Inhibitors
COX-2: A New Anti-inflammatory Drug Target
Arachidonic acid
Glucocorticoids
COX-2
(Inducible)
COX-1
(Constitutive)
(–)
·
·
·
·
X
(–)
TARGET FOR A
SPECIFIC COX-2
INHIBITOR
NSAIDs
Stomach
Intestine
Kidney
Platelet
Inflammatory site:
· Macrophages
· Synoviocytes
· Endothelial cells
COX-2 Selectivity:
Molecular Basis
NSAID Binding Clefts
COX-1
COX-2
Chemical Structures of Oxicams and Coxibs
OXICAMS
COXIBS
Linear, enolic acid
Y-shaped, Tricyclic
CH3
Meloxicam
OH
O
S
N
H
S
O
NH2
O
Celecoxib
S
O
N
N N
CF3
N
CH3
O
H3C
O
CH3
Piroxicam
OH
S
O
Rofecoxib
O
O
O
CH3
O
S N
N
O
N
H
COX-2 Selectivity
DRUG
Rofecoxib
Celecoxib
Meloxicam
Diclofenac
Indomethacin
COX-2 IC50/COX-1 IC50
.013
.080
.200
.170
1.500
Efficacy as an emerging concern of
NSAID used
Potency (strong)
 Onset of action (rapid)
 Duration of action (long)

•Efek samping minimal
•Harga terjangkau
Meloxicam (MOVI-COX) was approved recently by the
FDA for use in osteoarthritis.
The recommended dose for meloxicam is 7.5 to 15 mg
once daily for osteoarthritis and 15 mg once daily for
rheumatoid arthritis.
Meloxicam demonstrates roughly tenfold COX-2 selectivity
on average in ex vivo assays. However, this is quite
variable, and a clinical advantage or hazard has yet to be
established. There is significantly less gastric injury
compared to piroxicam (20 mg/day) in subjects treated
with 7.5 mg/day of meloxicam, but the advantage is lost
with 15 mg/day
(Goodman & Gilman, 2006)
Potency of NSAID
milligram basis of active compound for each formula
potency
NSAID
strong Meloxicam
Piroxicam
Diclofenac
moderate Celecoxib
Nimesulide
Ketorpofen
weak Mefenamic acid
Naproxen
Nabumetone
mg/formula
7.5, 15
10, 20
25, 50, 75
100, 200
100
100, 200
500
500
500
Onset of action of NSAID
onset
NSAID
T-max (hr)
Rapid Diclofenac
0.8
Nimesulide 1.2 – 2.7
Slow Celecoxib
2–4
Meloxicam
6
Duration of action of NSAID
duration
NSAID
short Diclofenac
Nimesulide
moderate Celecoxib
Naproxen
long Meloxicam
Piroxicam
T-1/2 (hr)
1.1
1.8 – 4.7
11
14
20
57
TOXICITY OF NSAIDs
Ototoxic
Bronchospam
Color blindness
CHF
Hepatotoxic
UGIB
Perdarahan
GI
Bleeding
Nephrotoxic
Allergy
Tocolytic
Mechanism of = Mechanism of
therapeutic effects
adverse effects
Table IV. Incidence of gastrointestinal (GI) adverse events
No. of
patients
Drug
exposure
(days)
Patients/
byear
No. of GI
adverse
events
Percentage
per 100
patients/year
736
56
113
0
0
Meloxicam
7.5mg
10158
33
918
3
0.3
Meloxicam
15mg
2960
179
1451
9
0.6
Meloxicam
22.5mg
910
241
600
6
1
Diclofenac
5464
35
524
9
Naproxen
243
117
78
1
1.7
1.3
Treatment
Placebo
Efficacy and Tolerability of Meloxicam, a COX-2 Preferential Nonsteroidal Anti-Inflammatory Drug
[Clin Drug Invest 22(12):799-818, 2002. © 2002 Adis International Limited]
Kombinasi OAINS
Kombinasi 2 OAINS:



Tidak dianjurkan
Efek samping meningkat
Tidak menambah efikasi
Kombinasi OAINS
dengan Pelindung
Lambung:

Kombinasi OAINS dan
Analgetik:
Masih dapat
dipertanggungjawabkan

Ditujukan untuk sedikit
mengatasi masalah efek
samping terhadap
lambung.
Dapat diberikan bersama
golongan PPI,
Misoprostol
NSAID +Acetaminophen
 Greater
analgesic effect than either
alone
 Avoids adverse effects of opioids
 Similar half lives for many NSAIDS
and acetaminophen
 Over-the-counter
 Each has analgesic ceiling.
Pain: A conceptual approach to treatment
(Biopsycosocial approach)
Anti-depressants /
psychotropics
Cognitive therapies
Functional restoration
Pain Behaviors
Suffering
Opioid
Relaxation
Spiritual
Pain
Perception
Adjuvants
NSAIDs?
Acetaminophene
Neural augmentation
Ablative surgery
Local block
Nociception
NSAIDs (Movicox ®)
Surgery
Physical modalities
1. Looser JD, Cousins MJ. Med J aust 1990;216: 153-208; 2. van den Hout JH, et al. Clin J Pain. 2003;19:87-96.; 3.
Mynors-Wallis L, et al. Br J Psychiatry. 1997;170:113-119.; 4. Morley S, et al. Pain. 1999;80:1-13.
Anamnesa nyeri secara sistematik dan
teratur
Berprasangka baik (percaya) terhadap
keluhan pasien atau keluarga
Carilah metode kontrol nyeri yang nyaman
untuk pasien dan keluarga
Dilakukan intervensi yang tepat
waktunya, logis dan terkoordinasi
Edukasi pasien dan keluarga untuk
mengatasi nyeri sekuat mungkin